The health of the oral cavity is maintained by salivary secretions. Our past studies focused on understanding mechanisms of saliva formation, their alteration during pathology, and developing novel methods to treat salivary dysfunction. During this reporting period we continued to utilize gene transfer technology to alter salivary epithelial cells to address clinical and biological questions. Specifically, we focused on two major problems resulting from use of recombinant adenoviral vectors: transient transgene expression and a potent immune response. To extend expression we have used recombinant adeno-associated virus vectors, and developed a unique hybrid vector incorporating both adenoviral and retroviral elements. Both approaches lead to more stable expression in rodent glands. Two ways to manipulate the immune response were tried; a drug, clodronate, to deplete glands of phagocytic cells, and coadministration of vectors encoding either IL-4 or IL-10. Both methods were unsuccessful. We showed that transgenes contain sorting signals recognized by glands in vivo, that lead to specific patterns of polarized protein secretion. We also made progress towards the development of an orally implantable, first generation artificial salivary gland. - salivary glands, gene therapy, adenovirus, AAV, hybrid vectors, radiation damage, Sjogren's syndrome, secretion, biomimetics